Amyloid beta (Aβ) species have been shown to play a key role in neuropathology of Alzheimer's Disease (AD); however the exact roles that soluble Aβ species and insoluble amyloid plaques play remain controversial. In past decades, much effort has been put into the research dealing with amyloid plaques, and most of the drug developments for AD have been oriented to eliminate plaques or reduce the formation of these plaques by different approaches. Several drugs, such as the aggregating inhibitor tramiprosate, the humanized monoclonal antibody bapineuzumab, and the γ-secretase inhibitor Flurizan, were developed and underwent clinical trials. Unfortunately, these clinical trials, by and large failed to prove the effectiveness of those drugs. These failures may have been due to poorly organized patient recruitments, which may have been due to a lack of accurate diagnoses to distinguish AD-dementia from other dementia, and to the inability to link the Aβ loading with the degree of dementia. This strongly indicates that reliable diagnoses are essential and, further, consideration should be given to drug development based on the presence of amyloid pro-plaque species, particularly soluble Aβ species.
There are currently no available techniques to reliably monitor the soluble Aβ species in vivo. In recent years, researches have demonstrated that positron emission tomography (PET) can be used as an imaging modality to detect AD pathology. Probe PIB is used for the purpose of early clinical diagnosis, but not for early stages of pathology (it is widely believed that the AD pathology stages are not synchronized with the clinically diagnosed stages, and the correlations between the clinical stage and the degree of pathological abnormality is still unclear).
Molecular optical imaging is a promising modality for early AD pathological detection. Multiphoton and near infrared imaging are the most used optical imaging modalities, based on the fluorescent property of the probes. Although multiphoton microscopy could be very useful in animal research, it is invasive and only provides a very small field-of-view. Near Infrared Imaging (NIR) is a very attractive tool for early AD detection because it has an acceptable depth penetration, is non-invasive, and requires inexpensive instrumentation.
Previous studies have suggested that amyloid plaque burden correlates poorly with Alzheimer's disease (AD) severity. Mounting evidences from recent years have pointed towards the toxicity of the soluble monomeric species as the first manifestation of AD. However, detection of these species in vivo presents an unsolved problem. Most of the techniques such as MRI, PET, and optical imaging used for in vivo detection of AD abnormalities have been focused on plaque imaging. Methods that are capable of detecting soluble Aβ species in vivo are urgently needed. It can be appreciated that these methods will be beneficial for early and accurate diagnosis of AD, and in addition will be helpful for AD drug development.